Novel process for producing fused imidazopyridine derivatives and novel crystal form

ABSTRACT

The present invention provides a process of a compound of the formula (I):  
                 
 
     wherein R is heteroaryl or the like, ring A is a heteroalicyclic group or the like comprising reacting a compound of the formula (II):  
                 
 
     wherein Hal is halogen and the other symbols are the same as the above, in the presence of a sulfinic acid salt and further in the presence of an acid or a salt with an organic base, and a novel crystal form of 2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridine phosphate monohydrate.

TECHNICAL FIELD

[0001] The present invention relates to a novel synthetic process and anovel crystal form of condensed imidazopyridine derivatives which areuseful for pharmaceuticals.

BACKGROUND ART

[0002] Condensed imidazopyridine derivatives of the present inventionare compounds described in JP 1993/286973A and known to be useful aspsychotropic agents, antianxiety agents, anesthesia antagonistic agents,and cerebral function activators. In the above publication, a method forproducing the condensed imidazopyridine derivatives which are cyclizedby using N-methyl-2-pyrrolidone, biphenyl ether-biphenyl mixture etc. isdescribed. But it was very difficult to use this method for industrialproduction because it is necessary to react at 150° C. to 250° C.

[0003] This publication only describes that2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridineor salts thereof were obtained just as white crystals and does notindicate preferable crystal forms of phosphate or phosphate monohydrate.

[0004] Abstract of the 23rd Congress of Heterocyclic Chemistry,pp.97-99, 1992 discloses a reaction for obtaining heterocyclic sulfonylcompounds from its chloro compounds by using a sulfinic acid salt as acatalyst and thus obtained sulfonyl compounds are easily reacted bynucleophilic substitution of carbanions. But the publication does notsuggest an affection by addition of a catalyst such as an acid or a saltof an organic base, specifically methanesulfonic acid.

DISCLOSURE OF INVENTION

[0005] The object of the present invention is to provide a novelsynthetic process of condensed imidazopyridine derivatives, specifically2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridineor salts thereof and a novel crystal form of phosphate salt thereof.

[0006] The present invention provides

[0007] [1] A process for producing a compound of the formula (I):

[0008] wherein R is optionally substituted aryl or optionallysubstituted heteroaryl and ring A is a 5- to 9-membered alicyclic groupwhich may contain one or more of O, S, SO, SO₂ and/or NR¹ (wherein R¹ ishydrogen, alkyl, esterified carboxy, carbamoyl or acyl) and which may besubstituted with alkyl (hereinafter referred to as Compound (I)), apharmaceutical acceptable salt or solvate thereof

[0009] comprising reacting a compound of the formula (II):

[0010] wherein Hal is halogen and the other symbols are the same as theabove (hereinafter referred to as Compound (II)) in the presence of asulfinic acid salt,

[0011] [2] The process as described in [1], wherein the reaction iscarried out in the presence of a) an acid or b) a salt with an organicbase,

[0012] [3] The process as described in [1] or [2] wherein R is3-isoxazolyl and ring A is

[0013] [4] The process as described in any one of [1] to [3] wherein thesulfinic acid salt is a para-toluenesulfinic acid salt,

[0014] [5] The process as described in any one of [2] to [4] wherein theacid is methanesulfonic acid,

[0015] [6] The process as described in any one of [2] to [5] wherein thereaction temperature is 120° C. or lower,

[0016] [7] A crystal of2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridinephosphate monohydrate of the formula (Ia):

[0017] (hereinafter referred to as Compound (Ia)), which has a powderX-ray diffraction pattern having main peaks at diffraction angle(2θ)=15.3, 17.8, 26.2, 11.6, 20.9, 25.7 and 27.9 (degree) and

[0018] [8] The crystal as described in [7] which has a melting point of162 to 175° C.

BRIEF DESCRIPTION OF DRAWINGS

[0019]FIG. 1 shows powder X-ray diffraction chart of prism crystals.

[0020]FIG. 2 shows infrared absorption spectrum chart of prism crystals.

[0021]FIG. 3 shows powder X-ray diffraction chart of needle crystals.

[0022]FIG. 4 shows infrared absorption spectrum chart of needlecrystals.

BEST MODE FOR CARRYING OUT THE INVENTION

[0023] In the present description, “halogen” includes fluorine,chlorine, bromine and iodine. Chlorine is preferable.

[0024] In the present specification, the term “aryl” includes phenyl,naphthyl, anthryl, indenyl, phenanthryl and the like.

[0025] The term “optionally substituted aryl” includes the abovementioned “aryl” which may have one or more of substituents selectedfrom alkyl, hydroxy, alkoxy, aryloxy, acyloxy, carboxy, ester (e.g.,alkoxycarbonyl, aralkoxycarbonyl etc.), cyano, amino, mono- ordi-substituted amino, hydrazino, hydroxyamino, halogen, nitro, acyl,carbamoyl, thiocarbamoyl, carbamoyloxy, thiocarbamoyloxy, ureido,thioureido, sulfonamide, mono- or di-substituted sulfonamide, sulfonicacid, halogenoalkyl, hydroxyalkyl, alkoxyalkyl, acyloxyalkyl,nitroalkyl, aminoalkyl, acylaminoalkyl, cyanoalkyl, carboxyalkyl and thelike. Preferable examples are substituted or unsubstituted phenyl andthe examples of substituents for phenyl are methyl, methoxy, chloro andthe like.

[0026] The term “heteroaryl” means a cyclic group containing one or moreof hetero atoms optionally selected from O, S and N in the ring and thecyclic group may condense with a carbocycle or another heterocycle. Theexamples of “heteroaryl” are 5- to 6-membered heteroaryl such aspyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl,thiazolyl, thiadiazolyl, furyl, thienyl etc., and condensed heteroarylsuch as indolyl, benzimidazolyl, indazolyl, indolizinyl, quinolyl,isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl,quinoxalinyl, pteridinyl, benzisoxazolyl, benzoxazolyl, oxadiazolyl,benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl,benzofuryl, benzothienyl, carbazolyl, phenazinyl etc.

[0027] As the substituents for “optionally substituted heteroaryl”,exemplified are alkyl, hydroxy, alkoxy, carboxy, ester (e.g.,alkoxycarbonyl, aralkoxycarbonyl etc.), cyano, amino, mono- ordi-substituted amino, hydrazino, hydroxyamino, halogen, nitro, acyl,carbamoyl, thiocarbamoyl, carbamoyloxy, thiocarbamoyloxy, ureido,thioureido, sulfonamide, mono- or di-substituted sulfonamide, sulfonicacid, halogenoalkyl, hydroxyalkyl, alkoxyalkyl, acyloxyalkyl,nitroalkyl, aminoalkyl, acylaminoalkyl, cyanoalkyl, carboxyalkyl and thelike. These substituents may substitute at one or more of possiblepositions. The substituents are preferably unsubstituted 5-memberedheteroaryl, more preferably unsubstituted thienyl, unsubstituted furyl,unsubstituted isoxazolyl or unsubstituted pyridyl, and most preferablyunsubstituted isoxazolyl.

[0028] “A 5- to 9-membered alicyclic group which may contain one or moreof O, S, SO, SO₂ and/or NR¹ wherein R¹ is hydrogen, alkyl, esterifiedcarboxy, carbamoyl or acyl, and which may be substituted with alkyl”condenses with the neighboring pyridine ring. The examples of alicyclicgroups are a carbocyclic group such as a cyclopenteno ring, acyclohexeno ring, a cyclohepteno ring, a cycloocteno ring, a cyclononenoring etc., a heteroalicycle such as pyrrolidino, pyrrolino,imidazolidino, pyrazolidino, dihydrothiopheno, dihydrofurano,thiazolino, dihydropyranno, dihydrothiopyrano, piperidino, piperazino,morpholino, thiomorpholino, tetrahydropyridino, and tetrahydropyrimidinoetc. Dihyclropyrano, dihydrothiopyrano or piperidino is preferable anddihydropyrano is especially preferable. These rings may be substitutedwith alkyl (e.g., one or two methyl, ethyl or the like).

[0029] The term “alkyl” includes a straight or branched alkyl having 1to 10 carbon atoms and a lower alkyl having 1 to 6 carbon atoms ispreferable. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,tert-pentyl, 2-metbylbutyl, n-hexyl, isohexyl, heptyl, isoheptyl, octyl,isooctyl, nonyl, decyl and the like are included.

[0030] The alkyl parts of “halogenoalkyl”, “hydroxyalkyl”,“alkoxyalkyl”, “acyloxyalkyl”, “nitroalkyl”, “aminoalkyl”,“acylaminoalkyl”, “cyanoalkyl” and “carboxyalkyl” are the same as theabove “alkyl”.

[0031] The term “esterified carboxy” includes alkoxycarbonyl,aryloxycarbonyl and aralkoxycarbonyl and the like. The examples aremethoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyland the like.

[0032] The term “acyl” includes an aliphatic acyl having 1 to 10 carbonatoms and an aromatic acyl. The examples are formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioloyl,methacryloyl, crotonoyl, cyclohexanecarbonyl, benzoyl, 4-nitrobenzoyl,4-tert-butylbenzoyl, benzenesulfonyl, toluenesulfonyl and the like.

[0033] The term “alkoxy” includes straight or branched alkoxy having 1to 10 carbon atoms and a lower alkoxy having 1 to 6 carbon atoms ispreferable. The examples are methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy,neopentyloxy, tert-pentyloxy, 2-methylbutoxy, n-hexyloxy, isohexyloxy,heptyloxy, isoheptyloxy, octyloxy, isooctyloxy, nonyloxy, decyloxy andthe like.

[0034] The alkoxy parts of “alkoxycarbonyl”, “alkoxyalkyl” and“aralkoxycarbonyl” are the same as the above “alkoxy”.

[0035] The aryl parts of “aryloxy”, “aryloxycarbonyl” and“aralkoxycarbonyl” are the same as the above “aryl”.

[0036] The acyl parts of “acyloxy”, “acylaminoalkyl” and “acyloxyalkyl”are the same as the above “acyl”.

[0037] The substituents for “mono- or di-substituted amino” and “mono-or di-substituted sulfonamide” include one or two of hydroxy, halogen,alkyl, alkenyl, acyl, aryl and the like.

[0038] “Compound (I)” includes any possible pharmaceutically acceptablesalt of each compound. As the “pharmaceutically acceptable salt”,exemplified are salts with mineral acids such as hydrochloric acid,sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid,hydrobromic acid and the like; salts with organic acids such as formicacid, acetic acid, tartaric acid, lactic acid, citric acid, fumaricacid, maleic acid, succinic acid, methanesulfomc acid, benzenesulfonicacid, p-toluenesulfonic acid and the like; salts with acidic amino acidssuch as ornithine, aspartic acid, glutamic acid and the like. Phosphateis preferable.

[0039] Compound (I) includes solvate thereof, wherein arbitrary numbersof suitable organic solvent or water molecules may coordinate toCompound (I). Hydrate is preferable and monohydrate is more preferable.

[0040] Compound (I) includes three kinds of tautomers and the abovementioned formula ) is just an example. Compound (I) includes othertautomers, i.e., Compound (I′) having double bonds at the 2-3,3a-3b and4-5 position and Compound (I″) having double bonds at the 1-3b, 2-3 and3a-4 position of the following formulae.

[0041] Compound (I) can be obtained from Compound (II) by the followingreactions.

[0042] Compound (II) is reacted in a suitable solvent such asdimethylformamide, dimethylsulfoxide, N, N-dimethylimidazolidinone,N-methylpyrrolidone, dimethylacetoamide and Dautherm A in the presenceof a sulfinic acid salt for several tens minutes to several hours. Theexamples of a sulfinic acid salt are sodium para-toluenesulfinate,potassium para-toluenesulfinate, lithium para-toluenesulfinate, sodiummethanesulfinate, potassium methanesulfinate and lithiummethanesulfinate. The upper limit of the reaction temperature is around150° C., preferably around 145° C. and lower limit is around 90° C.,preferably around 100° C.

[0043] The above reaction is preferably subjected to further in thepresence of “an acid” or “a salt with an organic base” in addition tothe presence of a sulfinic acid salt. The examples of “an acid” aremethanesulfonic acid and para-toluenesulfinic acid. “A salt with anorganic base” is preferably a salt which has pKb 5 or lower, forexample, hydrochloride or hydrobromide with pyridine,N-methylmorpholine, N,N-dimethylpyridine or the like, hydrochloride,hydrobromide or methanesulfonate of Compound (I).

[0044] When the desired compounds are synthesized in the presence of “a)an acid or b) a salt with an organic base” and a sulfinic acid salt, thereaction may be conducted at about 130° C. or lower, preferably about120° C. or lower, and most preferably about 100° C. or lower. The lowerlimit for suitably conducting this reaction is about 90° C., preferablyabout 100° C.

[0045] The present reaction which is conducted in the presence of anacid or a salt with an organic base is very useful for inexpensive andsimple industrial production of Compound (I) because of escaping thehigh temperature reaction described in JP 1993/286973 A.

[0046] Compound (I) obtained by the present method can be turned into afree compound, hydrochloride, methanesulfonate, maleate, phosphate orthe like by the conventional method. For example, methanesulfonate canbe turned into a free compound by treating with sodium hydroxide. A freecompound can be crystallized as phosphate by treating with an aqueoussolution containing phosphoric acid (for example, 20% aqueousisopropanol).

[0047] Two kinds of crystal forms, i.e., prism crystals and needlecrystals were found as crystals of Compound (Ia), one of Compound (I)which can be obtained by the above method. These crystals aredistinguished by characteristic peaks of powder X-ray diffraction orabsorption bands of infrared absorption spectrum.

[0048] For example, prism crystals can be obtained by the followingmethod.

[0049] Firstly, a free compound, a salt or solvate of2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridineis obtained by the method described in JP 1993/2286973A or theabove-mentioned method. Thus obtained compound (for example, phosphate)is suspended in a diluted aqueous solution of phosphoric acid (about0.01 equivalent, preferably 0.05 equivalent). The suspension is stirredor allowed to stand under cooling or at room temperature for severalhours to recrystallize, and needle crystals of Compound (Ia) areobtained.

[0050] Free compound or hydrate of2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridinemay be crystallized as phosphate from an aqueous solvent (for example,aqueous methanol, aqueous ethanol, aqueous propanol, aqueous isopropanoland the like, preferably 20% aqueous isopropanol) containing phosphoricacid at the mole ratio of 1 to 2, preferably 1.2. Then, the obtainedcrystals may be recrystallized from a diluted aqueous solution ofphosphoric acid in the similar manner as the above.

[0051] Thus obtained needle crystals are suspended in a diluted aqueoussolution of phosphoric acid again and are kept with stirring or onstanding for about 1 to 3 days to obtain prism crystals. Prism crystalsof Compound (Ia) can be obtained when needle crystals are stirred withheating at about 30 to 100° C., preferably 60 to 100° C. for severaltens minutes to several hours. When recrystallization is carried out byadding seed crystals already prepared, the desired crystals are obtainedeffectively.

[0052] Prism crystals of Compound (Ia) are preferable because of highstability to heat and light as compared with needle crystals. Prismcrystals have another advantage of good operation in synthetic processesbecause they are easily separated from a solvent by filtration.Furthermore, prism crystals are stable and high quality at ordinarytemperature and atmospheric pressure because water molecules arecontained in prism crystal structure as crystal water by making hydrogenbinding.

[0053] Melting point of prism crystals of Compound (Ia) is 162 to 175°C., more closely 167 to 170° C. The determination can be conductedaccording to the melting point determination method in pharmacopoeia ofJapan.

[0054] The present invention is further explained by the followingExamples and Experiments, which are not intended to limit the scope ofthe present invention.

EXAMPLES

[0055] In the following Examples, X-ray diffraction of Compound (Ia) wasdetected under the following conditions.

[0056] X-ray diffraction conditions:

[0057] Rigaku Corporation RAD-C, powder X-ray diffraction meter

[0058] Target: Cu, Graphite Monochrometer, Tube voltage: 40 kV, Tubecurrent: 40 mA, Slit:

[0059] DS=0.5, RS=0/3, SS=0.1, Scan Speed: 3°/min, Detector Scintilationcounter,

[0060] Sample cell: small diameter, for small amount of samples (φ 5 mm)

Example 1 Synthesis of2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridine

[0061] 1.25 g of Compound (II: Hal is Cl, R=3-isoxazolyl, ringA=dihydropyrano) was dissolved in 12 ml of DMF and 3.20 g of sodiumpara-toluenesulfinate was added. The solution was heated to 110° C. and0.86 g of methanesulfonic acid was added. Solution of 3.75 g of Compound(II) in 12.5 ml of DMF was added dropwise over 1 hour at the sametemperature. After the mixture was stirred for 1.5 hours at the sametemperature and cooled, 40 ml of acetone was added to obtain a crudemixture salt (methanesulfonic acid salt and hydrochloride) of the titledcompound.

[0062] Without drying, the obtained mixture salt was dissolved in 55.5ml of water. 0.367 g of 96% sulfuric acid and 0.25 g of activated carbonwere added and the mixture was stirred at 60° C. After cooling,activated carbon was filtered off and 18.5 g of 4.8% sodium hydroxidewas added to neutralize. Crystallized crystals were filtered to obtain3.99 g of free compound dihydrate of the title compound (80% yield).

Example 2

[0063] Using a similar method of Example 1 except that the kind ofsulfinic acid salt and existence or absence of acid, the desiredcompounds were synthesized and the affection of a sulfinic acid salt andacid was examined. Synthesized compound was2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridinehydrochloride, which is described in JP 1993/286973 A. Number of moleequivalent in tables means the volume per 1 mole equivalent of Compound(II) and “1V” means 1 ml per 1 g of Compound (II). TABLE 1 Reactiontemperature Reaction Yield sulfinic acid salt acid solvent (° C.) time(hr) (%) Lithium 1 mole — — DMSO 145 1 92.0 para-toluene- equivalent(2V) sulfinate Lithium 0.5 mole   — — DMSO 145 2 93.0 para-toluene-equivalent (2V) sulfinate Sodium 0.5 mole   — — DMSO 145 2 90.5para-toluene- equivalent (2V) sulfinate Sodium 1 mole Methane- 0.5 moleNMP 94-97 1 90.4 para-toluene- equivalent sulfonic equivalent (4V)sulfinate acid Sodium 1 mole Methane- 0.5 mole NMP 94-97 2 94.0para-toluene- equivalent sulfonic equivalent (4V) sulfinate acid

Reference Example 1 Synthesis of2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridine(free compound, dihydrate)

[0064] After 984 g of Compound (II: Hal=Cl, R=3-isoxazolyl, ringA=dihydropyrano) (3.53 mol) was added in a 5 L 4 necked flask equippedwith a stirrer, a thermometer and a nitrogen gas tube, 1.97 L ofN-methyl-2-pyrrolidone was poured therein to obtain a suspension. Thesuspension was reacted with stirring under mild nitrogen atmosphere for50 minutes at 190 to 210° C. (internal temperature) in oil bath of 200°C. After the reacted mixture was cooled to 40° C., 2 L of acetone wasadded to obtain the suspension. The obtained suspension was poured intoa 20 L 4 necked flask, 7.84 L of acetone was added and the mixture wascooled to 3° C. The precipitated crystals were filtered, washed twicewith 1.3 L of acetone and air-dried for 18 hours to obtain 879 g ofcrude crystals of2-(3-isoxazolyl)-3,6,7,9-tetrahydroimisazo[4,5-d]pyrano[4,3-b]pyridine(hydrochloride) (89.3%).

[0065] 879 g of crude crystals were dissolved in 35.16 L of 20% aqueousisopropanol with heating and 505 ml of concentrated aqueous ammonia and295 g of activated carbon were added. After the solution was refluxedfor 20 minutes and activated carbon was filtered off, the filtrate waswashed with 6.7 L of warmed 20% aqueous isopropanol and 3.3 L ofisopropanol. The filtrate and wash liquid were mixed and concentratedunder reduced pressure to obtain 9.95 kg of a concentrated solution. Theobtained solution was cooled at 4° C. for 18 hours, precipitatedcrystals were filtered, washed twice with 1.8 L of ice-cooled 20%aqueous isopropanol and air-dried for 18 hours to obtain 764 g of thetitled compound (77.8%).

[0066] mp>300° C.

[0067] Elementary Analysis (C₁₂H₁₀N₄O₂.2H₂O) Calcd.: C, 51.80; H, 5.07;N, 20.13; H₂O, 12.95%. Found: C, 51.85; H, 5.10; N, 20.30; H₂O, 12.71%.

Reference Example 2 Preparation of Needle Crystals

[0068] To 764 g of the compound obtained in Reference Example 1 (freecompound, dihydrate) in a 30 L reaction chamber, 26.75 L of 20% aqueousisopropanol was added and dissolved with stirring under heating at 80 to84° C. 76.4 g of activated carbon was added and the mixture was stirredfor 30 minutes at the same temperature. After the activated carbon wasfiltered off, the activated carbon was washed with 3.4 L of warmed 20%aqueous isopropanol. The filtrate and wash liquid were mixed andtransported to a 60 L crystallizer. The solution was warmed to 78° C. todissolve precipitated crystals, a solution of 389 g of 85% phosphoricacid (1.23 mol equivalent) in 389 ml of isopropanol was added and thedropping vessel was washed with 400 ml of isopropanol. Though needlecrystals were precipitated after one minute and the whole mixture wassolidified, it turned to be a suspension by stirring at high speed. Thusobtained suspension was cooled to 4° C. and allowed to stand for 18hours. After the suspension was took out from the crystallizer, it wasfiltered, washed twice with 4.6 L of isopropanol and air-dried at roomtemperature for 18 hours to obtain 946.5 g of Compound (Ia) as needlecrystals (96.2%).

[0069] mp 234-236° C.

[0070] Elementary Analysis (C₁₂H₁₀N₄O₂.H₃PO₄.H₂O) Calcd.: C, 40.23; H,4.22N, 15.63; P, 8.65; H₂O, 5.03%. Found: C, 40.39; H, 4.17N, 15.92; P,8.53; H₂O, 4.10%.

[0071] powder X-ray diffraction: 12.4, 14.7, 17.4, 19.6, 21.4, 25.0,27.0 (degree)

[0072] IR: 3426, 3109, 1642, 1123, 998, 957 and 808 (cm⁻¹)

Example 3 Preparation of Prism Crystals

[0073] To 3119 g of needle crystals (8.705 mol) obtained in ReferenceExample 2 in a 30 L enamel bat equipped with a stirrer, 18.71 L ofdistilled water containing 50.18 g of 85% phosphoric acid (0.05 molequivalent) was added to obtain a suspension. Crystalline nucleusalready prepared was added and stirred at room temperature (23 to 24°C.) for 43 hours. The precipitated crystals were filtered, washed twicewith 1.5 L of ice-cooled distilled water and dried under reducedpressure at room temperature for 4 days to obtain 2902 g of Compound(Ia) as prism crystals (93.1%).

[0074] mp 167 to 170° C. (formed fusion)

[0075] dp 242 to 252° C. (colored fusion)

[0076] Elementary Analysis (C₁₂H₁₀N₄O₂.H₃PO₄.H₂O) Calcd.: C, 40.23; H,4.22N, 15.63; P, 8.65; H₂O, 5.03%. Found: C, 40.25; H, 4.26N, 15.71; P,8.64; H₂O, 5.16%.

[0077] powder X-ray diffraction: 11.6, 15.3, 17.8, 20.9, 25.7, 26.2 and27.9 (degree)

[0078] IR: 3264, 3104, 2533, 2085, 1648, 1119, 1089, 954 and 513 (cm⁻¹)

[0079] In the following Experiments, contents of Compound (I) weredetermined by HPLC under the following conditions.

[0080] Device: WATERS 510, 481, 712 WISP, 741, FD20A or

[0081] WATERS 510, 486, 712 WISP, 741, FD20A

[0082] Column: YMC-packed column AM-302 S-5 120A ODS (4.6 mm φ×150 mm)

[0083] Column temperature: room temperature

[0084] Mobile phase: methanol/water/TFA=200/800/1 (v/v)

[0085] Flow rate: 1.0 ml/min

[0086] Wave length: 230 nm

[0087] Concentration: 5-85 μg/ml

[0088] Injection Volume: 15 μl

[0089] Purity of Compound (I) was observed by HPLC peaks detected byWATERS 991 Photodiode Array Detector.

[0090] Experiment 1 Stability to Heat

[0091] Prism crystals and needle crystals of Compound (Ia) were used forsamples. About 25 mg of each crystal was put in a small glass containerwith polyethylene cap. Containers were capped, sealed with PARAFILM andkept at 40° C., relative humidity of 75% for 6 months. Prism crystalswere not observed appearance transition and needle crystals changed itscolor to pale yellow.

[0092] These results show prism crystals are more stable to heatcompared with needle crystals.

[0093] Experiment 2 Stability to Light

[0094] After samples were prepared in the same manner of Experiment 1and sealed, they were kept under 1800 Lux exposure (16 hours exposureper day of a fluorescent lamp, 28800 Lux*hr/day) or under 10000 Luxexposure (continuous exposure of a fluorescent lamp, 240000 Lux*hr/day,average temperature 30±3° C.). As a standard reference sample, each ofcrystals was put in a sealed container and kept at −20° C. The contentof crystals were determined by the absolute calibration curve methodusing HPLC under the above conditions. Results of observation ofappearance transition and remaining rate are shown below. TABLE 2 Prismcrystals Needle crystals appear- remaining appear- remaining ance rate(%) ance rate (%) 1800Lux 1 month − 100.0 ± or + 98.6 2 months − 99.9 +98.3 3 months − or ± 100.1 ++ 96.9 4 months ± 100.1 ++ 97.0 10000Lux 1week ± 99.5 ± or + 99.3 2 weeks ± or + 99.7 + 98.0 3 weeks + 99.2 + or++ 97.4

[0095] As shown the above, needle crystals changed the color to yellowand their remaining rate decreased after 3 months. Prism crystalsscarcely changed appearance and their remaining rate are more stable tolight.

INDUSTRIAL APPLICABILITY

[0096] As shown in the above examples and experiments, the presentprocess of Compound (I) is useful for mass-production. Prism crystals ofCompound (Ia) is exhibiting high stability and very useful forpharmaceutical raw materials.

1. A process for producing a compound of the formula (I):

wherein R is optionally substituted aryl or optionally substitutedheteroaryl and ring A is a 5- to 9-membered alicyclic group which maycontain one or more of O, S, SO, SO₂ and/or NR¹ (wherein R¹ is hydrogen,alkyl, esterified carboxy, carbamoyl or acyl) and which may besubstituted with alkyl, a pharmaceutical acceptable salt or solvatethereof comprising reacting a compound of the formula (II):

wherein Hal is halogen and the other symbols are the same as the above,in the presence of a sulfinic acid salt.
 2. The process as claimed inclaim 1, wherein the reaction is carried out in the presence of a) anacid or b) a salt of an organic base.
 3. The process as claimed in claim1 or 2 wherein R is 3-isoxazolyl and ring A is


4. The process as claimed in any one of claims 1 to 3 wherein thesulfinic acid salt is a para-toluenesulfinic acid salt.
 5. The processas claimed in any one of claims 2 to 4 wherein the acid ismethanesulfonic acid.
 6. The process as claimed in any one of claims 2to 5 wherein the reaction temperature is 120° C. or lower.
 7. A crystalof2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridinephosphate monohydrate of the formula (Ia):

which has a powder X-ray diffraction pattern having main peaks atdiffraction angle (2θ)=15.3, 17.8, 26.2, 11.6, 20.9, 25.7 and 27.9(degree).
 8. The crystal as claimed in claim 7, which has a meltingpoint of 162 to 175° C.